4-(pyrrolyl)-salicylic acid derivatives

ABSTRACT

New salicyclic acid compounds, particularly 4-(heterocyclic)salicylic acid derivatives and process for their preparation are claimed. The new 4-(heterocyclic)salicyclic acid compounds described have anti-inflammatory, anti-pyretic and analgesic activity.

United States Patent Shen et al. Aug. 29, 1972 [54] 4-(PYRROLYL)-SALICYLIC ACID A, 260/347.3, 424/232 DERIVATIVES [51] Int. Cl. ..C07d 27/20 [72] inventors: Tsung Ying She, westfield; [58] Field of Search ..260/326.3

goIward Jones, l-lolmdel, 60th of Prim Examiner Alex Maze] Assistant ExaminerJoseph A. Narcavage [73] Assignee: Merck & Co,, Inc,, Rahway, NJ, AttorneyMichael C. Sudol, J12, Harry E. Westlake,

. Jr. and I. Louis Wolk [22] Filed: June 22, 1970 21 Appl. No.: 48,479 1 ABSTRACT New salicyclic acid compounds, particularly 4- [52] C] 260]3263260250R 260,250 A (heterocyclic)-salicylic acid derivatives and process 260/251 R, 260/256.4 R, 260/256.4 C, 260/290 R, 260/296 R, 260/297 R, 260/302 R, 260/302 D, 260/306.8 R, 260/306.8 D, 260/307 R, 260/307 H, 260/309, 260/332.2

for their preparation are claimed. The new 4-(hetero cyclic)salicyclic acid compounds described have antiinflammatory, anti-pyretic and analgesic activity.

3 Claims, No Drawings 1 4-(PYRROLYL)-SALICYLIC ACID DERIVATIVES BACKGROUND OF THE INVENTION The development of anti-inflammatory compounds in the past two decades has seen the growth of a great many new drugs. Most of these have been steroids of the ll-oxygenated pregnane series. These, while highly effective, have the drawback of causing many side effects. There is a need in the market for equally effective compounds of much simpler structure and having less side effects.

SUMMARY OF THEINVENTION DESCRIPTION AND PREFERRED EMBODIMENTS This invention relates to new heterocyclic phenyl compounds and to processes for producing the same. More specifically, it relates to 4-(heterocyclic)-salicylic acid compounds (2-hdroxy -4-heterocyclic benzoic acids). Still more specifically, this invention relates to compounds having the following general formula:

R2 R1 H COOH wherein Het is a 6- membered ring structure containing from one to three hetero atoms or a five-membered ring structure containing from one to four hetero atoms. The hetero atoms are either nitrogen, sulphur, or oxygen;

R, is hydrogen, lower alkyl, lower alkoxy, halogen, or

halo lower alkyl;

R; is hydrogen, alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or pentyl), halo (such as, chlorine, bromine or iodine or fluorine), amino, alkyl amino, (preferably lower alkyl amino, such as methyl amino or isopropyl amino), dialkyl amino, (preferably diloweralkyl amino such as dimethyl amino or diethyl amino), hydroxy or alkoxy (preferably lower alkoxy, such as methoxy or ethoxy).

Preferable examples of the six-membered ring structure containing from one to three hetero atoms are 2,3 or 4-pyridyl, 2 or 3 pyrazinyl, 2,4 or S-pyrimidyl, 3 or 4 pyridazinyl, s-triazinyl, 3,4 or b-as-triazinyl (1,2,3- triazinyl; 1,3,5-Triazinyl; l ,2,4-triazinyl).

Preferred examples of five-membered heterocyclic ring structures containing from one to four hetero atoms are:

2 or 3 furyl,

2 or 3 thienyl,

2,4 or S-thiazolyl,

3 or 4(B 1,2,5-thiadiazolyl),

2 or5-( 1,3,4-thiadiazolyl),

3 or 5-(-B (1,2,4-thiadiazolyl),

2,4 or 5-oxazolyl,

3,4 or 5-isooxazolyl,

1,2 or 3-pyrrolyl,

1,2 or 4-imidazolyl.

The most preferred heterocyclic ring structures are the oxazole, thiazolyl and pyrole rings in that order of importance.

In all the above structures, the R substituent on the heterocyclic nucleus can be in any available position and may be in one or more positions.

Representative compounds of this invention are as follows:

4( N-pyrrolyl)-salicylic acid,

4-((2-oxazolyl)-selicylic acid,

4-( 2-thienyl)-salicylic acid,

4-(2-pyridyl)-salicylic acid,

4-( 3-pyridyl)-salicylic acid,

2-hydroxy-4-(4'-pyrimidyl)-benzoic acid,

3-hydroxy-4-(2'-thiazolyl)-benzoic acid.

We have found that the compounds described above have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation. In addition, some of them have a useful degree of anti-pyretic and analgesic activity. For these purposes, they are normally administered orally in tablets or capsules, the optimum dosage depending on the particular compound being used and the type and severity of the condition being treated. Although the optimum quantities to be used will depend on the compound employed and the particular type of disease treated, oral dose levels of preferred compounds in the range of 50 mg. to 10 g. per day are useful in the control of said conditions, depending on the activity of the specific compound and the reaction sensitivity of the patient.

The compounds of the instant invention can be prepared by a carboxylation reaction wherein the appropriate starting material is reacted with carbon dioxide, preferably in the presence of potassium carbonate. The reaction is usually carried out in a pressurized vessel at a wide range of temperatures especially from about 50 to 200 C., preferably at about 175 C. at 800 p.s.i. initial pressure. The pressure can also vary from atmospheric pressure on up. The reaction mixture is carried out for a sufficient time to consume the stoimetric amount of carbon dioxide. When the reaction is complete, the desired product can be isolated by extraction with water, the water layer then acidified and the precipitated product recrystallized.

Various other methods for preparing the end products 'are shown in the following examples. Also, the following examples should be construed as illustrations of the invention and not limitations thereof.

EXAMPLE 1 EXAMPLE Preparation of 4-(2-oxazolyl-salicylic acid A. m-(Diethoxy ethylaminomethyl)-nitrobenzene 22.7 Gms. (0.15 moles) of 3-nitro-benzaldehyde and 20.0 gms. (0.15 moles) of diethoxyethyl amine were mixed together and heated in an oil bath for about 1 hour until no more water is given off. The mixture was then cooled and diluted with an ether-hexane mixture at which time a solid material crystallized. The solid material was filtered and dried yielding 34.3 gms. of m- (diethoxy ethylaminomethyl)-nitrobenzene, m.p. 4244 C. B. m-(2'-Oxazolyl)-nitrobenzene A mixture of 65 of phosphorus pentoxide and 20 ml. of concentrated sulfuric acid was added to a threenecked flask, and the mixture heated to 185-190 C. To this mixture was added another mixture composed of 175 gms. of m-(diethoxy ehtylaminomethyl) nitrobenzene, dissolved in 175ml. of cold concentrated sulfuric acid. The entire mixture was then refluxed at 190 C. for approximately one-half hour. The mixture was cooled and poured onto ice, at which time a solid precipitated. The solid was filtered and recrystallized from an ethanol-water mixture to yield approximately 4.5 gms. of m-(2-oxazolyl)-nitrobenzene, m.p. 9295 C C. 2-(m-Aminophenyl)-oxazole 2.5 Gms. of m-(2-oxazolyl)-nitrobenzene was added in a hydrogenation bomb to 0.5 gm. of percent pal ladium on carbon and 250 ml. of ethyl alcohol. Hydrogen gas was added under pressure until the uptake was complete. The reaction mixture was then filtered and the filtrate concentrated to dryness to yield 2.2 gms. of 2-(m-aminophenyl)-oxazole, m.p. 66.06 5.5C. D. 2-(m-Hydroxyphenyl)-oxazole A solution of 390 ml. (2.44 moles) of 2-(maminophenyl)-oxazole in 10 ml. of 2N sulfuric acid was prepared and cooled in an ice bath. To this mixture was added a solution of 190 ml. (2.75 moles) of sodium nitrite in 2 ml. of water. The reaction mixture was stirred at room temperature for 10 minutes and then in 55 C. for 0.5 hour and finally at room temperature overnight. The reaction mixture was then extracted with ethylene dichloride, the ethylene dichloride separated, dried with magnesium sulfate, and concentrated to yield a crude solid. The crude solid was recrystallized from an ethylene dichloride-hexane solvent and yielded substantially pure Z-(m-hydroxyphenyl)-oxazole. E. 4-(2-Oxazolyl)-salicylic acid 480 mg. of 2-(m-hydroxyphenyl)-oxazole and 1.7 gms. of potassium carbonate were ground together and dried overnight at 60 C. under high vacuum. The mixture was subjected to 4,500 p.s.i. of carbon dioxide in a glass tube in a pressure bomb. The temperature was raised to 250 for 6 hours. After cooling and venting the contents of the bomb are taken up in 100 ml. of water and filtered. Hydrochloric acid was added to give a precipitate which was collected and dried in a vacuum oven. The precipitate recrystallized from an ethanol-water mixture to yield 4-(2-oxazolyl)-salicylic acid, m.p. 255-25 8 C.

EXAMPLE 3 Preparation of 4-(2-thiazolyl)-salicylic acid A. m-Cyanoanisole 25 Gms. of m-cyanophenol, 30 gms. of dimethyl sulfate, and 155 ml. of 2N sodium hydroxide were stirred at room temperature for 1 hour. The mixture was extracted with two 150 m1. portions of ethyl ether. The ether layer was then washed with water, dried and evaporated to yield m-cyanoanisole as a colorless oil. B. 3-Methoxyben2ylthioamide 19.0 Gms. of m-cyanoanisole and 22 gms. of thioacetarnide were dissolved in ml. of dimethyl formamide. The reaction mixture was stirred while hydrogen chloride gas was bubbled in. During the addition of the hydrogen chloride gas, the color of the reaction mixture went from pale yellow to dark red. After 20 minutes, the reaction mixture was heated on a steam bath for 20 minutes more, cooled and poured into 150 mol. of water. The mixture was extracted with three 100 ml. portions of ethyl ether. The ether mixture was washed with water and the ether then evaporated to yield 20.5 gms. of 3-methoxybenzylthioamide as a dark red oil. C. 3-(2-Thiazolyl)-anisole 20.5 gms. of 3-methoxybenzylthioamide and 24.6 gms. of B-bromoacetaldehyde diethylacetol were mixed together and dissolved in percent ethyl alcohol with 5 ml. of concentrated hydrochloric acid. The mixture was refluxed for 3 hours and cooled, at which time pale yellow needles crystallized out. These crystals were filtered and the solid dried at 70 C. under vacuum for 3 hours. A yield of 14.2 gms. of 3-(2- thiazolyl)-anisole thiazolyl)-anisole resulted, m.p. 200-202 C. D. 3-(2-Thiazolyl)-phenol 14.0 Gms. 3-(2-'lhiazolyl)-phenol 3-(b 2-thiazolyl)- anisole was added to 63ml. of 48 percent hydrobromic acid and the mixture refluxed for 2 hours. The reaction mixture was then cooled in an ice bath, basified by the addition of sodium bicarbonate and again cooled. The solid precipitate which formed was filtered and dried to yield 2.1 gms. of 3-(2-thiazolyl)-phenol, m.p. 137142 C. E. 4-(b 2-Thiazolyl)-salicylic acid 5.6 gms. of 3-(2-thiazolyl)-phenol and 12.0 gms. of potassium'carbonate were subjected to 4,700 p.s.i. of carbon dioxide in a glass tube in a pressure bomb at 180 for 6 hours. After cooling and venting the contents of the bomb are taken up in ml. of boiling water and filtered. Hydrochloric acid was added and the precipitate filtered. The solid was then dried in an oven to yield 1.2 gms. of 4-(2-thiazolyl-salicylic acid, m.p. 247250 C.

EXAMPLE 4 Preparation of 4-[4-( 2-chlorothiazolyl)]-salicylic acid A. a-Thiacyanato-m-methoxyacetophenone A hot saturated solution of potassium thiocyanato (43.5 gms.) in 30 ml. of water was added to a warm 500 ml. solution of 50.0 gms. of m-methoxyphenacyl bromide. The reaction mixture was allowed 50.0 stand at room temperature for 3 hours. The mixture was poured into 1 l. of water and the undissolved solid was filtered and dried. There was obtained 43.0 gms. of athiocanato-m-methoxyacetophenone, m.p. 6870 C. B. 3-Chloro-4-((m-methoxyphenyl)-thiazole Hydrogen chloride gas was bubbled into a suspension of 5.0 gms. of a-thiocyanato-m-methyoxyacetophenone in 200 ml. of ether, the reaction mixture being cooled in an ice bath during the 1.5 hours. After about 45 minutes, solution was effected and after another -25 minutes a precipitate started to form. The precipitate was filtered and decomposed to the parent thiazole by stirring for a few minutes in a dilute sodium carbonate solution. In this way the crude hydrochloride salt of 2-chloro-4-(m-methoxyphenyl)- thiazole was obtained, m.p. 64-68 C. C. 2-Chloro-4-(m-hydroxyphenyl )-thiazole 5.0 gms. of boron tribromide was added to a suspension of 2.0 gms. of 2-chloro-4-(m-methoxyphenyl)- thiazole in ml. of methylene dichloride. The reaction mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture and a white solid (1,8 gms.) precipitated, m.p. 150160C.

This solid was a boron complex of 2-chloro-4-(mhydroxyphenyl)-thiazole. It was decomposed by heating it with a saturated sodium bicarbonate solution for about one-half hour on a steam bath. The crude solid was filtered, dried and crystallized from petroleum ether. A yield of 0.9 g. of 2-chloro-4-(m-hydroxyphenyl)-thiazole was obtained, n1.p. 89-90 C. D. 4-[4-(2-chlorotl'iiazolyl)]-salicylic acid 2,3 gms. of 2-chloro-4-( m-hydroxyphenyl)-thiazole and 5.1 gms. of potassium carbonate were subjected to a pressure of 4,0005,000p.s.i. of carbon dioxide at 175 C. for 8 hours. The 85 was vented and the crude product added to 100 ml. of water on the steam bath, a brown oil separated. The supernantent liquid was decanted off. The brown residue solidified at room temperature and was sublimed at 200 C. 85mg. of 4-[4-(2- chlorothiazolyl)]-salicylic acid was obtained, m.p. l85-1 86 C.

EXAMPLE 5 Preparation of 4-(4-thiazolyl)-salicylic acid A. 4-(m-Methoxyphenyl )-thiazole 5.78 gms. of 2'chloro-4-(-methoxyphenyl)-thiazole, 5.0 gms. of palladium on carbon, 200 ml. of methanol,

and 20 ml. of 10 percent sodium hydrochloric acid were put into a hydrogen bomb and the reaction mixture hydrogenated at room temperature and 30 p.s.i. hydrogen pressure until the uptake of hydrogen ceases. The palladium catalyst was filtered off and the filtrate concentrated to 25 ml. and diluted with 50 ml. of water and an amber oil separated. The oil was extracted with ether, dried, and concentrated down to give 3.0 gms. of 4-(m-methoxyphenyl)-thiazole as an amber oil. B. 4-(m-Hydroxyphenyl)-thiazole 3.0 gms. of 4-(m-methoxyphenyl-)-thiazole was added to 10 ml. of concentrated hydrochloric bromic acid and the mixture refluxed for 5 hours. Upon cooling a solid appeared, which was filtered. The solid was taken up in dilute sodium hydroxide and neutralized. The solid precipitate which appeared was filtered and recrystallized from chloroform to yield 2.1 gms. of 4- (m-hydroxyphenyl)-thiazole, m.p. 1 l8l20 C.

C. 4-(4-Thiazolyl)-salicylic acid 2.1 gms. of 4-(m-hydroxyphenyl)-th1azole was added R2 R fill 400. kJ

wherein is pyrrolyl;

R is hydrogen, lower alkyl, lower alkoxy, halogen or haloloweralkyl; and

R is hydrogen, lower alkyl, halo, amino, lower alkylamino, di( lower a1kyl)amino, hydroxy or lower alkoxy.

2. The compound of claim 1, wherein R and R are hydrogen.

3. The compound 4-N-pyrrolyl-salicylic acid. 

2. The compound of claim 1, wherein R1 and R2 are hydrogen.
 3. The compound 4-N-pyrrolyl-salicylic acid. 